ABSTRACT Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1-2% of the population, and about 8% of individuals over 80 years of age. AF has been identified as the leading cause of thromboembolic events such as stroke. Every hour, approximately 15 patients with AF will suffer from a stroke in the US. Although prevention of cardioembolic stroke is clinically and economically critical, traditional oral anticoagulation therapy does not have satisfactory compliance, along with number of drawbacks. It is estimated that more than 90% of thrombi responsible for thromboembolic events in AF form in the left atrial appendage (LAA) due to its narrow apex (blind end), unsmooth inner surface, and irregular contraction. Excision or exclusion of the LAA with devices provides a novel treatment strategy for preventing thromboembolic events in AF patients. There are two types of devices; i.e., epicardial suture/clip, which closes the LAA from outside the heart, and endocardially deployed occluder, which eliminates the dead space from the inside. The current devices have some significant disadvantages, however, such as high cost, foreign body retention, migration, etc. The epicardial device seems to achieve better results than endocardial device but the epicardial approach is harder to access. In this Phase I proof of concept proposal, the objective is to partially invert the LAA endoluminally to make it resorb over time. This best of both world approach (efficacy of clipping or resorption through an endoluminal approach) should be superior to existing devices and methods. The hypothesis is that the inversion of the LAA will change the stress distribution (homeostasis) in the appendage by reducing the tensile stress and even create some compressive stresses in the tissue where a reduction in stress or compression will cause resorption as per growth-stress law. The major deliverable is to demonstrate the safety of LAA inversion as assessed by EKG, echocardiography, histology, cardiac biomarkers, and neurohormones to establish a new paradigm of LAA resorption as opposed to LAA occlusion or exclusion. Our preliminary data show feasibility of this approach in a swine model where the partial inversion of LAA was implemented surgically and endovascularly and found to eliminate the LAA dead space. In the open-chest procedure in swine, we performed measurements at 4 weeks post-surgery, showing the inversion of LAA is safe (no arrythmia, no hemodynamic or cardiac changes) and effective (LAA was resorbed). Compared to current LAA closure devices, our approach leaves nothing behind (i.e., no implanted device) and hence will be safer and much less expensive. This innovative concept along with the development of percutaneous method for this purpose will not only provide a new treatment for the prevention of AF related embolic events but also reduce human, social and economic burden of stroke.